CN103553932B - Method suitable for industrially preparing memanitine hydrochloride - Google Patents
Method suitable for industrially preparing memanitine hydrochloride Download PDFInfo
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Abstract
The invention discloses a method for preparing memanitine hydrochloride. The method comprises the steps of carrying out ritter reaction on 1-bromo-3,5-dimethyladamantane and acetonitrile under the action of concentrated sulfuric acid to synthesize 1-actamido-3,5-dimethyladmantane, hydrolyzing the 1-actamido-3,5-dimethyladmantane under the alkaline condition to obtain 1-amino-3,5-dimethyladmantane, acidifying 1-amino-3,5-dimethyladmantane with hydrochloric acid to obtain crude memantine, and recrystallizing the crude product to obtain a fine product. According to the method, temperature is controlled in the first-step acetyl-amination process when the system color changes, thus being capable of effectively preventing heat release due to fierce reaction, reducing the danger and being beneficial to industrialization; ethyl acetate or dichloromethane is selected for extraction solution, thus being capable of avoiding the use of high-toxicity benezene or chloroform; the mixed solution of ethanol or isopropanol andethyl acetate is selected for recrystallization, thus being capable of avoiding the use of high-toxicity chloroform.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of preparation method treating Alzheimer disease drugs memantine.
Background technology
Nineteen eighty-two memantine by Merz company with trade(brand)name Akatinol first Germany go on the market, also completed the clinical study of three phases in the U.S. and other various countries of European Union, be about to listing.Memantine be first be used for the treatment of in-nmda receptor antagonist of severe Alzheimer's disease (be called for short AD), the excessive release of major excitatory neurotransmission neurotransmitters glutamate can be suppressed, alleviate because the neuronal cell that L-glutamic acid excessively discharges, calcium ion is too much caused is poisoning, damage and dead, thus improve symptom and the function problem of dementia patients, have and feature that is good by property, drug safety simultaneously.Therefore, this medical instrument has wide economic and social profit.
The synthetic method of memantine salt is more, specific as follows:
Method one: acetonitrile method.The patents such as US3391142A for raw material, first pass through Ritter Reactive Synthesis 1-acetylaminohydroxyphenylarsonic acid 3 with bromo-3, the 5-dimethyladamantanes of 1-, 5-dimethyladamantane, then hydrolysis obtains MEM in the basic conditions, finally obtains memantine with hcl acidifying salify.
Method two: Wyler's process.Patent US4122193 ﹑ CN1400205A and CN1544415 is with 1-bromo-3,5-dimethyladamantane is raw material, urea obtains 1-acetylaminohydroxyphenylarsonic acid 3 as amidation reagent synthesis, 5-dimethyladamantane, then hydrolysis obtains 1-amino-3,5-dimethyladamantane, finally obtains memantine with hcl acidifying salify.
Method three: schematized version.US Patent No. 5599998 is with 1-bromo-3,5-dimethyladamantane is raw material, under ultrasound condition, 1-lithium-3 is obtained by reacting with lithium methide, 5-dimethyladamantane, 1-lithium-3,5-dimethyladamantane and ammonium chloride are obtained by reacting 1-amino-3,5-dimethyladamantane, last acidifying salify obtains memantine.
Method four: chloro method.Patent US5061703 ﹑ CN1193981C and CN1488622A for raw material, obtains 1-chloro-3,5-dimethyladamantanes by tertiary butyl chloride chlorination with 1,3-dimethyladamantane, is obtaining memantine through Anization ﹑ hydrolysis and salify.
Method five: methane amide method.Patent WO2009115334A2 proposes with 1,3-dimethyladamantane for raw material, obtains 1-formamido group-3,5-dimethyladamantane, then obtain memantine through acidifying salify by amidated.
Method six: nitrofication process.Patent CN101412678A reports with 1,3-dimethyladamantane for raw material, obtains 1-nitro-3,5-dimethyladamantane by digestion reaction, through H
2reduction obtains MEM, and last acidifying salify obtains memantine.
Method seven: directly ammoniation process.Patent CN1556094A proposes with 1,3-dimethyladamantane is raw material, and in bromine effect, next step completes Xiu Dai ﹑ Ritter and reacts, and obtains 1-amino-3 without separation of intermediates direct Chun Xie ﹑ hydrolysis, 5-dimethyladamantane, last acidifying salify obtains memantine.
In the above-mentioned methods, method two urea is as amidation reagent, and temperature of reaction is higher, and reaction conditions is very harsh.Method three grignard reaction needs anhydrous and oxygen-free condition, and needs ultrasonic device, and operation is harsh, requires higher to operator.First method four needs to carry out chloro with aluminum chloride and tertiary butyl chloride in anhydrous conditions, and need in chlorination process constantly to add aluminum chloride, troublesome poeration, and the activity of chloro thing is not high, reaction conversion ratio is low.Method five produces a large amount of nitrogen peroxide steam in reaction process, and needs during aftertreatment to neutralize with a large amount of alkali.Method six needs to use hydrogen and Pd/C catalyzer, reacts more dangerous.The utilization ratio of method seven raw material is not high, and should " one kettle way " polystep reaction be carried out in same container, side reaction is more, wayward.US Patent No. 3391142A discloses the method for acetonitrile method synthetic hydrochloric acid memantine, with 1-bromo-3,5-dimethyladamantane is starting raw material, take acetonitrile as aminating agent, obtain 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane, then hydrolysis obtains 1-amino-3 in the basic conditions, 5-dimethyladamantane, last hydrochloric acid salify obtains memantine.Chinese patent CN01127788.2 improves extraction solvent and recrystallization solvent, extraction solvent chloroform replaces benzene, recrystallization process chloroform replaces volatile inflammable ethanol/ether mixed solvent, meanwhile, replaces expensive glycol ether when alcoholysis with cheap polyvalent alcohol.Chinese patent CN201110375931.6 glues thick ﹑ stirring difficulty for the first step acetyl amination reaction to be improved, and namely in reaction system, adds a certain amount of organic acid, thus is beneficial to stirring.We find by experiment, improved acetonitrile method still has some problems urgently to be resolved hurrily: the first step carries out meeting very exothermic when kharophen is reacted to a certain degree, react wayward when especially testing amplification, more dangerous, such as 1-bromo-3,5-dimethyladamantane input amount 100 grams, in reaction process, temperature can acutely rise to 160 DEG C, and material can spray; Hydrolysis reaction aftertreatment use extraction solvent adopt the larger chloroform of toxicity, large to human injury; What use during memantine recrystallization is also the chloroform that toxicity is larger.These problems can affect suitability for industrialized production, therefore, carry out reasonably improving particularly necessity to the method.
Summary of the invention
The present invention seeks to the weak point solving aforesaid method, a kind of optimum synthesis method of memantine is provided, this synthetic method effectively can solve very exothermic in amidate action process and bring dangerous problem, and provides a kind of to environment and the little extraction solvent of harm and recrystallization solvent.
For achieving the above object, the technical solution used in the present invention is: a kind of method preparing memantine, comprises the following steps:
The first step: bromo-for 1-3,5-diformazan fund firm alkane ﹑ acetonitriles and acetic acid mixing are placed in reaction flask, drip the vitriol oil under ice bath, in controlling, temperature is lower than 20 DEG C, after dropwising, removes ice bath,, there is colour-change in system, add ice bath in stirring at room temperature, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, drying obtains 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane.
Second step: by 1-acetylaminohydroxyphenylarsonic acid 3,5-diformazan fund firm alkane ﹑ second two alcohol ﹑ water and sodium hydroxide are placed in reaction flask, be heated to 150-160 DEG C, reaction 12h, is chilled to room temperature, with solvent extraction twice, merge organic phase, organic phase saturated common salt water washing, concentrated, obtain MEM.
3rd step: MEM and ethyl acetate are placed in reaction flask, drip concentrated hydrochloric acid under ice bath, reaction 1h, filters, obtains memantine crude product.The mixing solutions recrystallization of memantine crude product polar solvent and ester, obtains fine work.
In technique scheme, the mol ratio of 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane and sodium hydroxide is 1:1 ~ 10, and the volume ratio of water and ethylene glycol is 1:5 ~ 15.
In technique scheme, extraction solvent is selected from the one in ethyl acetate and methylene dichloride.
In technique scheme, polar solvent is selected from the one in Shui ﹑ Jia Chun ﹑ Yi Chun ﹑ Virahol and propyl carbinol; Ester is selected from the one in Yi Suan Yi Zhi ﹑ butylacetate and phenylacetate; The volume ratio of ester and polar solvent is 1:5 ~ 15.
In preferred technical scheme, the mol ratio of 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane and sodium hydroxide is 1:5.5, and the volume ratio of water and ethylene glycol is 1:10.
In preferred technical scheme, polar solvent is selected from ethanol or Virahol; Ester is selected from ethyl acetate; The volume ratio of ethyl acetate and ethanol or Virahol is 1:10.
Reaction process can be expressed as:
The present invention is relative to the advantage of additive method:
(1) temperature control when system color changes in the first step kharophen process, can effectively prevent from reacting very exothermic, reduces dangerous, is conducive to industrialization.
(2) extraction solution selects ethyl acetate or methylene dichloride, can avoid using the large benzene of toxicity or chloroform.
(3) recrystallization selects the mixing solutions of ethanol or Virahol and ethyl acetate, can avoid the chloroform using toxicity large equally, and yield is high.
Form is described in further detail content of the present invention more by the following examples, but should not be interpreted as in the above-mentioned subject area of the present invention at this point and be only limitted to following examples.Do not departing under the above-mentioned technology prerequisite of the present invention, the corresponding replacement made according to ordinary skill knowledge and customary means or the amendment of change, include within the scope of the invention.
Embodiment one:
(1) preparation of 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane
By bromo-for 1-3, 5-dimethyladamantane (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask, the vitriol oil is dripped under ice bath, in controlling, temperature is lower than 20 DEG C, after dropwising, remove ice bath, stirring at room temperature, colour-change is there is in system, from colourless become light yellow, light yellowly become scarlet, interior temperature is between 35 DEG C and 50 DEG C, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, drying obtains 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, 5-dimethyladamantane.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (88g, 0.397mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (88g, 2.20mol) be placed in reaction flask, be heated to 150-160 DEG C, reaction 12h, be chilled to room temperature, with dichloromethane extraction (150ml × 2), merge organic phase, organic phase saturated aqueous common salt (150ml) washs, anhydrous sodium sulfate drying, concentrated, obtain 69.5 grams of MEMs.
(3) preparation of memantine
Amino for 1--3,5-diformazan fund (69g, 0.385mol) ﹑ ethyl acetate (150ml) are placed in reaction flask, drip concentrated hydrochloric acid (43g) under ice bath, reaction 1h, filter, drying obtains 75 grams of memantine crude products.By the mixing solutions recrystallization of memantine crude product by Virahol (460ml) and ethyl acetate (46ml), be cooled to room temperature, then be placed in refrigerator 2h, suction filtration, drying obtains 57 grams of fine work, three step total recoverys 64%.
Embodiment two:
(1) preparation of 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane
By bromo-for 1-3, 5-dimethyladamantane (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask, the vitriol oil is dripped under ice bath, in controlling, temperature is lower than 20 DEG C, after dropwising, remove ice bath, stirring at room temperature, colour-change is there is in system, from colourless become light yellow, light yellowly become scarlet, interior temperature is between 35 DEG C and 50 DEG C, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, drying obtains 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, 5-dimethyladamantane.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (87g, 0.39mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (87g, 2.15mol) be placed in reaction flask, be heated to 150-160 DEG C, reaction 12h, be chilled to room temperature, be extracted with ethyl acetate (150ml × 2), merge organic phase, organic phase saturated aqueous common salt (150ml) washs, anhydrous sodium sulfate drying, concentrated, obtain 69 grams of MEMs.
(3) preparation of memantine
By MEM, (69g, 0.385mol) ﹑ ethyl acetate (150ml) is placed in reaction flask, drips concentrated hydrochloric acid (43g) under ice bath, and reaction 1h, filter, drying obtains 74.5 grams of memantine crude products.By the mixing solutions recrystallization of memantine crude product by Virahol (454ml) and ethyl acetate (45ml), be cooled to room temperature, then be placed in refrigerator 2h, suction filtration, drying obtains 56 grams of fine work, three step total recoverys 63%.
Embodiment three:
(1) preparation of 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane
By bromo-for 1-3, 5-dimethyladamantane (100g, 0.41mol) ﹑ acetonitrile (300ml) and acetic acid (100ml) mixing are placed in reaction flask, the vitriol oil is dripped under ice bath, in controlling, temperature is lower than 20 DEG C, after dropwising, remove ice bath, stirring at room temperature, colour-change is there is in system, from colourless become light yellow, light yellowly become scarlet, interior temperature is between 35 DEG C and 50 DEG C, add ice bath, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, drying obtains 88 grams of 1-acetylaminohydroxyphenylarsonic acids 3, 5-dimethyladamantane.
(2) preparation of MEM
By 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane (88g, 0.397mol) ﹑ ethylene glycol (700ml) ﹑ water (70ml) and sodium hydroxide (88g, 2.20mol) be placed in reaction flask, be heated to 150-160 DEG C, reaction 12h, be chilled to room temperature, with dichloromethane extraction (150ml × 2), merge organic phase, organic phase saturated aqueous common salt (150ml) washs, anhydrous sodium sulfate drying, concentrated, obtain 69.5 grams of MEMs.
(3) preparation of memantine
Amino for 1--3,5-diformazan fund (69g, 0.385mol) ﹑ ethyl acetate (150ml) are placed in reaction flask, drip concentrated hydrochloric acid (43g) under ice bath, reaction 1h, filter, drying obtains 75 grams of memantine crude products.By the mixing solutions recrystallization of memantine crude product by ethanol (250ml) and ethyl acetate (25ml), be cooled to room temperature, then be placed in refrigerator 2h, suction filtration, drying obtains 50 grams of fine work, three step total recoverys 56%.
Claims (3)
1. prepare a method for memantine, it is characterized in that, comprise the following steps:
The first step: bromo-for 1-3,5-diformazan fund firm alkane ﹑ acetonitriles and acetic acid mixing are placed in reaction flask, drip the vitriol oil under ice bath, in controlling, temperature is lower than 20 DEG C, after dropwising, removes ice bath,, there is colour-change in system, add ice bath in stirring at room temperature, continue reaction 12h, pour in frozen water, stir and separate out white solid, suction filtration, wash filter cake with water, drying obtains 1-acetylaminohydroxyphenylarsonic acid 3,5-dimethyladamantane;
Second step: by 1-acetylaminohydroxyphenylarsonic acid 3,5-diformazan fund firm alkane ﹑ second two alcohol ﹑ water and sodium hydroxide are placed in reaction flask, be heated to 150-160 DEG C, reaction 12h, is chilled to room temperature, with solvent extraction twice, merge organic phase, organic phase saturated common salt water washing, concentrated, obtain MEM;
3rd step: by 1-amino-3,5-dimethyladamantane and ethyl acetate are placed in reaction flask, concentrated hydrochloric acid is dripped under ice bath, reaction 1h, filter, obtain memantine crude product, the mixing solutions recrystallization of memantine crude product methyl alcohol, ethanol or Virahol and butylacetate or phenylacetate, obtains fine work.
2. preparation method according to claim 1, is characterized in that, extraction solvent is methylene dichloride.
3. preparation method according to claim 1, is characterized in that, the volume ratio of methyl alcohol, ethanol or Virahol and butylacetate or phenylacetate is 1:5 ~ 15.
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| WO2018082596A1 (en) * | 2016-11-03 | 2018-05-11 | Sunshine Lake Pharma Co., Ltd. | Solid forms of an adamantyl compound, compositions and uses thereof |
| CN111072491B (en) * | 2019-12-14 | 2022-11-04 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
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| CN1488622A (en) * | 2003-08-12 | 2004-04-14 | 江苏省原子医学研究所 | Method for preparing memantine hydrochloride |
| CN102432473A (en) * | 2011-11-23 | 2012-05-02 | 广州博济医药生物技术股份有限公司 | Synthetic method of memantine hydrochloride |
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| CN1488622A (en) * | 2003-08-12 | 2004-04-14 | 江苏省原子医学研究所 | Method for preparing memantine hydrochloride |
| CN102432473A (en) * | 2011-11-23 | 2012-05-02 | 广州博济医药生物技术股份有限公司 | Synthetic method of memantine hydrochloride |
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